The Role of Endoplasmic Reticulum Stress in Autoimmune-Mediated Beta-Cell Destruction in Type 1 Diabetes

Figure 2

Signaling pathways relevant to UPR. PERK, IRE1, and ATF6 act as ER stress sensors by binding to the ER chaperone BiP, and by which they remain inactive under normal condition. Upon the accumulation of unfolded proteins, BiP preferentially binds to the unfolded proteins, which results in the release of PERK, IRE1, and ATF6. Once released from BiP, PERK becomes activated and dimerized. Activated PERK phosphorylates eIF2α to suppress the overall transcription of mRNAs while selectively enhance the transcription of genes implicated in UPR such as the ATF4 mRNA, and through which ATF4 initiates the transcription of UPR target genes. Similar to PERK, IRE1 is dimerized and activated after detached from BiP. IRE1 induces XBP-1 by promoting the splicing of its mRNA. XBP-1 activates the transcription of its target genes to enhance UPR. The release of ATF6 from BiP results in the translocation of ATF6 to the Golgi apparatus, where ATF6 is cleaved and then translocates into the nucleus, and by which ATF6 initiates the transcription of target genes.